Basic ethers and process of making same



Patented Oct. 23, 1945 Karl Hoffmarin and Harald von Meyenburg, Basel, Switzerland, assignors to Ciba Pharmaceutical Products, Incorporated, Summit, N. J.

No Drawing. Application April 1, 1942, Serial No. 437,276. In Switzerland April 10, 1941 4 Claims. (p ece-471) It has been found that new basic ethers are obtained if disubstituted acetic acid esters, amides or nitriles which contain a hydroxyl group or a halogen atom in the a-position are caused to react with amino-alcohols or their reactive derivatives. As parent materials, use is made of those disubstitute'd acetic acid derivatives which contain aromatic, cycloaliphatic oraliphatic radicals as substituents, such as :e-diphenyl-e-hydroxy-, u-phenyl-a-alkyl-a-hydroxy-, a-phenyl-u-cyclohexyl-a-hydroxy-, or aioc-clicyclohexyl-oz-hydroxy-acetic acid ester or their a-halogen derivacarried out in the presence of solvents for example, ether, benzene, xylene and the like. If desired, it may take place in the presence of condensing agents, such as alkalis, alkali amides or alkali carbonates.

By addition of alkyl halides, alkylene halides, aryl sulfonic acid esters, dialkyl sulfates, or arylalkyl halides, quaternary ammonium compounds of the basic ether described above can be obtained in the usual manner.

If desired, the compounds obtained can be worked up still further. Thus, for example, the corresponding acids, esters or amides can be ob'- Grignard reaction) and these, in their turn, into ketones, by saponification.

The new basic ethers, which all contain four substituents at the carbon atom carrying the ether group, possess interesting pharmacological properties, in so far as they are strongly spasmolytically active. The new compounds are ap preciably more active than the comparable basically substituted ethers of the phenylacetic acid series, which contain only one substituent in addition to the ether group, such as, for example, a-

phenyl-a-diethylaminoethoxy-acetic acid ester.

The following examples illustrate the invention, but are not to be regarded as limiting it in any way.

tained from the nitriles, which, on the other hand, Amay also 'be converted into ketimides (by the Example 1 parts of benzilic acid ethyl ester are dropped in, and the reaction mixture is boiled under reflux until the reaction is complete. parts of chloroethyldiethylamine are now" introduced, heating is continued for ,4 hours under reflux, 1500 parts of absolute toluene are added, the ether is removed loy distillation, and the residue is heated for a further 4 hours on the water bath. On cooling, the reaction residue is extracted with dilute hydrochloric acid; the base is precipitated. by alkali as an oil and is taken up in ether. The ethereal solution .is dried, evaporated and the residue distilled under a high vacuum. The arediphenyl-a-diethylaminoethoxyacetic acid ethyl ester distils at 148.15l C. under 0.08 mm. of mercury.

The same compound is obtained by the reaction of diphenyl-bromacetic acid ethyl ester with sodium diethylaminoethanolate in toluene solution.

If e-phenyl-u-alkyl-ahydroxyacetic acid esters are used as parent material, e-phenyl-a-alkyl-adiethylaminoethoxyacetic acid esters, for example, such as a-ethyl-, a-propyl or m-iSOlpIODYI derivatives, are obtained. In a similar manner, also, basic ethers of a-phenyl-u-cyclohexyl-a-hydroxy-, a:a-dicyclohexyl-a-hydroxy-, a-phenylu-naphthyl-u-hydroxy-, or diphenylene-e-hydroxy-acetic acid esters can be obtained.

Example 2 If the benzilic acid ethyl ester in Example 1 be replaced by 242 parts of benzilic acid methyl ester, 0a e-diphenyl-a-diethyl-amino-ethoxyacetic acid methyl ester is obtained in good yield. It distils at 164-165 C. under 0.14 mm. of mercury.

Example 3 If the benzilic acid ethyl ester in Example 1 be replaced by 270 parts of benzilic acid n-propylester, or u-diphenyl-u-diethylamino-ethoxyacetic acid-n-propyl ester, B. P. /0.13 mm. is obtained.

Example 4 idino-ethoxyacetic methyl ester of B. P. 170-173" C./;13 mm. and a:u-diphenyl-u-piperidinoethoxyacetic acid-n-propyl ester, B. P. 165-170 C./0.1 mm. are obtained.

Example If the chlorethyld-iethylamine in Example 1 be replaced by y-chlorpropyldiethylamine, aim-diphenyl a. diethylaminopropyl-oXy-acetic acid ethyl ester, B. P. 151-157 C./0.05 mm. is obtained.

Example 6 4.6 parts of sodium are caused to react with 24 parts of diethylaminoethanol in 200 parts of toluene. When the sodium has dissolved, the mixture is allowed to react with 54 parts of aid-diphenyl-a-bromo-acetonitrile (prepared by bromination of diphenylacetonitrile). The product is worked up as described in Example 1, and 01.10;- diphenyldiethylaminoethoxyacetonitrile is obtained as oil of highboiling point. If this nitrile be allowed to react in the usual manner with Grignard reagents, corresponding ketones are obtained. For example, by causing the nitrile to react with ethylmagnesiumbromide, diphenyl-diethylaminoethoxymethyl-ethy1ketone is obtained.

Example 7 2.3 parts of powdered sodium are covered with 200 parts of absolute ether, and 12 parts of dry diethylaminoethanol are added. The reaction mixture is heated under reflux until the sodium has dissolved. 24.5 parts of aZa-diPhGHyl-a-ChlOI- acetamide are introduced and the mixture is boiled for 8 hours under reflux whilst stirring. The ethereal solution is extracted with dilute hydrochloric acid, and aZa-diphEIlYl-w-difithYlaminoethoxyacetamide is precipitated from the acid solution by addition of a solution of potash.

What we claim is:

1. azel-Diphenyl a dialkylaminoalkoxy-acetic acid-alkyl esters.

2". l:ec-Diphenyl-a-diethylaminoetho-xy acetic acid ethylester.

3. The aza-diphenyl acetic acid alkyl esters Which also contain in oc-DOSltiOIl an amino-substituted aliphatic ether group.

4. A member selected from the group consisting of the e-arylza-aryh, a-aryl:a-alkyl-, m-aryl: eL-cycloalkyland a-cycloalkyl oc-CYCIO- alkylacetic acid esters, amides and nitriles which also contain in oc-POSitiOII an amino-substituted aliphatic ether group.

KARL HOFFMANN. HARALD VON MEYENBURG. 

